Heteroreceptor complexes implicated in parkinson’s disease

Abstract

Heteromerization alters GPCR recognition, G-protein activation, receptor signaling and trafficking, thus changing receptor protomer pharmacology and function. This review deals mainly with the A2AR-D2R and A1R-D1R heteroreceptor complexes, their balance with dopamine and adenosine isoreceptor complexes and their role in Parkinson’s disease and its treatment. The major technique used for the visualization of the heteroreceptor complexes in the brain was the proximity ligation assay. A1R-D1R and putative A1R-D1R-D3R heteroreceptor complexes appear to exist in the direct pathway. Upon agonist activation the A1R protomer exerts a brake on the D1R protomer signaling of these complexes reducing the activity of the direct pathway with reduction of movement initiation. D1R-NMDAR and D1R-H3R-NMDAR heteroreceptor complexes in the striatal glutamate synapses integrate synaptic and volume transmission, where in the former complexes the D1R protomer enhances NMDAR signaling with enhancement of movements. A2AR-D2R and A2AR-D2R-mGlu5R heteroreceptor complexes with antagonistic receptor-receptor interactions exist in the dorsal striato-pallidal GABA neurons mediating motor inhibition. The A2AR and mGlu5R antagonists synergize to increase D2R protomer signaling by removing the A2AR and mGlu5R brakes on the D2R protomer signaling and heterobivalent compounds built of A2AR and mGlu5R antagonists may specifically and substantially remove these brakes reducing motor inhibition with development of antiparkinson actions.